Spinal cord injury (SCI) disrupts neurological pathways controlling movement, sensation, and autonomic processes, commonly causing long-term impairments. The restoration of damaged spinal tissue continues to pose significant therapeutic challenges. The RISEUP project explores an innovative combinatorial therapy that integrates stem cell transplantation with µsPEFs delivered by an Electro-Pulsed Bio-Hybrid (EPB) device. This in silico study faithfully reproduces the in vivo experimental setup that will be applied within the project to assess EPB functionality and stimulation effects. By positioning the EPB numerical model over the thoracic vertebral region of interest in the ViZOO Neurorat anatomical rat model, and by implementing laminectomy and SCI, a virtual replica of the in vivo experiments is proposed, aiming to inform, in a prospective way, whether electric (E-)field intensities estimated by in vitro studies and microdosimetry and shown to be suitable for electroporation could be reached in vivo, in the complex and evolving environment of the injured spinal cord. To reflect the biological evolution of SCI over the stimulation time, two lesion phases were simulated. First, acute SCI represents the immediate post-injury environment, while chronic models capture the later phase characterized by altered conductivity and structural reorganization. This dual-phase approach allows for a more accurate assessment of the experiments. Finally, dosimetric assessment was computed and evaluated in terms of induced E-field distribution, and peripheral nerves response. Peak E-fields beneath the EPB ranged from 20 to 70 kV/m, sufficient for transient membrane permeabilization and stem cell activation. Field penetration improved in chronic lesions due to increased conductivity, with deeper median fields (∼2 kV/m) compared to acute models. Neurofunctional safety was evaluated by coupling the E-field output to axonal electrophysiological models of intercostal nerves. The findings demonstrate that the EPB device can deliver effective, localized stimulation with minimal off-target neural activation. Furthermore, temporal lesion evolution influences field distribution, underscoring the importance of phase-specific assessment. © 2026, © The Author(s)

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